Abstract A40: Targeting TBK1 promotes apoptosis in MEK-inhibitor resistant mutant NRAS melanoma cells

Abstract

Abstract Melanoma is a devastating form of skin cancer. Fifteen to twenty percent of melanoma patients have an activating mutation in the GTPase, NRAS. Despite advances in the targeted inhibitor treatment for mutant BRAF melanoma patients, the options for mutant NRAS patients remain poor. TANK-binding kinase 1 (TBK1) is an atypical IκB kinase family member that acts downstream of the RAS effector RalGEF but the role of TBK1 in melanoma is not known. We found that NRAS overexpression in wild-type NRAS melanoma cells increased TBK1 phosphorylation. In a panel of NRAS mutant melanoma cells, we characterized sensitivity to MEK inhibition in 2D as well as 3D cell cultures that mimic the dermal microenvironment. We show that there is a differential response to MEK inhibition in this panel. TBK1 inhibition, through either siRNA transfection or pharmacological inhibitors, cooperated with MEK inhibition to promote apoptosis. These effects were particularly noted in those NRAS mutant cell lines that are insensitive to MEK inhibition. By contrast, this effect was absent in melanoma cell lines wild type for NRAS. These results identify TBK1 as a downstream effector for NRAS mutant melanoma and as a potential target for use in combinatorial therapy in this subset of patients for whom current therapeutic options are limited. Citation Format: Ha Linh Vu, Andrew E. Aplin. Targeting TBK1 promotes apoptosis in MEK-inhibitor resistant mutant NRAS melanoma cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A40. doi: 10.1158/1557-3125.RASONC14-A40